Exosomes in the Diagnosis and Treatment of Renal Cell Cancer

Abstract

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC.

Keywords: exosomes; mRNA; miRNA; renal cell cancer; tumor drug resistance; tumor microenvironment.

Figure 1

Structure and production of exosomes. (a) Structure of exosome depicting the molecular components; the phospholipid bilayer (blue colored) encloses the vesicle. Internally, the vesicle consists of cargo comprising nucleic acids, proteins, and lipids. (b) The biogenesis of exosomes involves (1) cargo from the extracellular space entering the cytosol through internalization wherein it forms the early endosome. (2) Early endosomes mature to form multivesicular bodies (MVBs) consisting of intraluminal vesicles that include tetraspanin (CD9, CD63, and CD81), an endosomal sorting complex required for transport (ESCRT) proteins (Alix, TSG101), integrins, heat shock proteins, cytoskeletal proteins, and membrane transport proteins. (3) Cargo internalization consists of cargo delivery from the trans-Golgi network and the cytosol. (4) MVBs consisting of exosome cargo are transported to the plasma membrane (PM) with the help of a microtubule network and Rab GTPases. (5) SNAREs dock the MVBs to the PM and ILVs are secreted as exosomes [21,22]. Created with BioRender.com, accessed on 15 August 2023.

Figure 2

The RTK inhibitor sunitinib in combination therapy with ketoconazole in RCC. The exosomes secreted from tumor cells affect the cells in the tumor microenvironment, leading to drug resistance and immune escape. The ESCRT pathway is one of the central components responsible for the biogenesis of exosomes. Lipids such as ceramide are generated by neutral sphingomyelinase (nSMAse-2), which is necessary for vesicle budding during ILV formation. Rab GTPases lead to the docking of MVBs to the plasma membrane (PM). Ketoconazole leads to the downregulation of Alix, nSMAse-2, and Rab27a, inhibiting exosome biogenesis and secretion and leading to a decrease in tumor growth [159,160]. Created with BioRender.com, accessed on 15 August 2023. Abbreviations—VEGFR: vascular endothelial growth factor receptor; PDGFR: platelet-derived growth factor receptor: ILV: intraluminal vesicles: ESCRT: endosomal sorting complex required for transport; MVB: multivesicular bodies: PM: plasma membrane.